臨床研究等提出・公開システム

A Phase 3, Double-Blind, Placebo-controlled Study of Quizartinib Administered in Combination with Induction and Consolidation Chemotherapy, and Administered as Continuation Therapy in Subjects with Newly Diagnosed FLT3 ITD (+) Acute Myeloid Leukemia

Phase 3 study of quizartinib

539

The median (min, max) age of the total population was 56.0 (20, 75) years (56.0 [23,75] years for subjects in the quizartinib arm and 56.0 [20, 75] years for subjects in the placebo arm). The number of subjects in each treatment arm was well balanced within the age groups used for stratification at Randomization (<60 years and >=60 years). Slightly more than half of the subjects were female (quizartinib: 144/268 [53.7%]; placebo: 150/271 [55.4%]), and most subjects were White (quizartinib: 159/268 [59.3%]; placebo: 163/271 [60.1%]). A total of 80 (29.9%) and 78 (28.8%) subjects in the quizartinib and placebo arms, respectively, were Asian. The majority (455 [84.4%] subjects) of subjects had an ECOG PS score of 0 or 1 at Screening (221 [82.4%] subjects in the quizartinib arm and 234 [86.3%] subjects in the placebo arm). Forty-seven (17.5%) and 36 (13.3%) subjects in the quizartinib and placebo arms had an ECOG PS score of 2 at Screening, respectively.

Overall, a total of 3468 subjects were screened for participation in the study. There were 2929 subjects who were screen failures; the most common reason for screen failure was FLT3-ITD negativity. In total, 539 subjects were randomized into the study (268 subjects in the quizartinib arm and 271 subjects in the placebo arm), and 533 subjects received study drug treatment (265 subjects in the quizartinib arm and 268 subjects in the placebo arm). A total of 539 subjects (268 subjects in the quizartinib arm and 271 subjects in the placebo arm) were included in the ITT Analysis Set. Two hundred sixty-five subjects and 268 subjects received at least 1 dose of quizartinib or placebo, respectively, and were included in the Safety Analysis Set.

By SOC, the most frequently reported TEAEs in both treatment arms were gastrointestinal disorders (diarrhea, nausea, and vomiting), infections and infestations (pneumonia and sepsis), general disorders and administration site conditions (pyrexia, oedema peripheral, and fatigue), and blood and lymphatic system disorders (febrile neutropenia, neutropenia, thrombocytopenia, and anemia). Infections, blood disorders, metabolism disorders, investigations, and reproductive disorders occurred more frequently (higher incidence of >=5 percentage points [pp]) with quizartinib than with placebo, while musculoskeletal disorders occurred more frequently with placebo. By PT, among the most commonly reported TEAEs, the events of neutropenia, ALT increased, ECG QT prolonged, neutrophil count decreased, and headache occurred more frequently (>=5 pp higher incidence) in the quizartinib arm than in the placebo arm. Sepsis was reported in fewer subjects in the quizartinib arm than in the placebo arm (15 [5.7%] subjects and 28 [10.4%] subjects, respectively.

Treatment with quizartinib resulted in a statistically significant OS benefit compared with placebo (p = 0.0324, 2-sided stratified log-rank test). The HR (95% CI) was 0.776 (0.615, 0.979), corresponding to a 22.4% relative risk reduction of death in favor of the quizartinib arm during the study. The median OS (95% CI) was 31.9 (21.0, not estimable [NE]) months in the quizartinib arm compared with 15.1 (13.2, 26.2) months in the placebo arm.

The median (95% CI) EFS was 0.03 (0.03, 0.95) months in the quizartinib arm and 0.71 (0.03, 3.42) months in the placebo arm. There was no statistically significant difference between subjects in the quizartinib and placebo arms on the secondary endpoint of EFS (HR [95% CI] = 0.916 [0.754, 1.114], p = 0.2371 by stratified log-rank test). Rates of CR, CR with FLT3-ITD MRD negativity, and CRc with FLT3-ITD MRD negativity were similar between treatment arms. However, numerically higher CRc rates were observed in the quizartinib arm (192 [71.6%] subjects) compared with the placebo arm (176 [64.9%] subjects) and were primarily driven by higher rates of CRi in the quizartinib arm (45 [16.8%] subjects compared with the placebo arm (26 [9.6%] subjects).

Study AC220-A-U302 demonstrated that the addition of quizartinib to induction and consolidation chemotherapy followed by continuation monotherapy was associated with an OS benefit in the overall study population of newly diagnosed subjects with FLT3-ITD (+) AML. These results are considered a clinically meaningful improvement. The safety results demonstrated a manageable safety profile for quizartinib with monitoring and dose modification. There were no new safety concerns identified in the study.

July. 12, 2024

April. 25, 2024

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00464-6/fulltext

Yes

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Information: - Study Protocol - Statistical Analysis Plan (SAP) - Informed Consent Form (ICF) Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

completed

Feb. 05, 2018

Interventional

Multi-center, double-blind, placebo-controlled

treatment purpose

3

1. Newly diagnosed, morphologically documented primary AML or AML secondary to myelodysplastic syndrome or a myeloproliferative neoplasm (at Screening)
2. Eastern Cooperative Oncology Group performance status 0-2 (at Screening)

1. Diagnosis of acute promyelocytic leukemia (APL), chronic myelogenous leukemia in blast crisis
2. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy

Both

Newly diagnosed AML

investigational material(s)
Generic name etc : Quizartinib
INN of investigational material : Quizartinib
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Oral administration

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Oral administration

efficacy
Overall Survival
Overall survival, defined as the time from Randomization until death from any cause

safety
efficacy
pharmacokinetics
pharmacodynamics
Event Free Survival (EFS)
EFS is defined as the time from Randomization until the date of the earliest of any of the following:
1. Refractory disease (or treatment failure) which is determined within 42 days of the start of the last cycle of induction chemotherapy
2. Relapse after CR
3. Death from any cause at any time during the study
Complete Remission (CR) Rate at the End of Induction
Composite CR Rate at the End of Induction, etc
Percentage of Participants Achieving CR With FLT3-ITD Minimal Residual Disease Negativity
Percentage of Participants Achieving Composite CR With FLT3-ITD Minimal Residual Disease Negativity, etc

-

Aug. 16, 2017